The potential role of nemonoxacin for treatment of common infections

Introduction: Nemonoxacin, a novel non-?uorinated quinolone, exhibits potent activity against Gram-positive bacteria, including MRSA and fluoroquinolone-resistant MRSA, Gram-negative and atypical pathogens. This agent also has a reduced propensity for resistance development in many kinds of pathogens.

Areas covered: This article reviews currently available clinical and in vitro data that support the potential role of nemonoxacin for the treatment of common infectious diseases, including community-acquired pneumonia (CAP), Clostridium difficile infections (CDIs), acute bacterial skin and skin structure infections (ABSSSIs) and sexually transmitted diseases (STDs). One recent Phase II trial comparing either 500 mg or 750 mg oral nemonoxacin with 500 mg oral levofloxacin for mild to moderate CAP demonstrated that nemonoxacin had comparable clinical success with levofloxacin. Nemonoxacin showed lower MICs against clinical C. difficile isolates than commercially available fluoroquinolones, making it a potential therapeutic agent if novel formulations are developed to maintain a higher concentration in the human gut. For STDs, nemonoxacin also showed good activity against some common pathogens, such as Chlamydia trachomatis and Neisseria gonorrhoeae.

Expert opinion: Although in vitro studies have shown promising results regarding the susceptibility to nemonoxacin of common pathogens causing CDIs, ABSSSIs and STDs, further clinical trials are needed to prove its efficacy.     

Dalbavancin for the treatment of acute bacterial skin and skin structure infections

Introduction: Acute bacterial skin and skin structure infections (ABSSSI) have increased in incidence and severity. The involvement of resistant organisms, particularly methicillin-resistant Staphylococcus aureus, presents additional challenges. The lipoglycopeptide dalbavancin has a prolonged half-life, high protein binding, and excellent tissue levels which led to its development as a once-weekly treatment for ABSSSI. In the pivotal DISCOVER 1 and DISCOVER 2 trials, dalbavancin proved non-inferior to vancomycin followed by linezolid when used sequentially for ABSSSI, forming the basis for its recent approval in the US and Europe for ABSSSI.

Areas covered: A literature search of published pharmacologic and clinical data was conducted to review the chemistry, pharmacodynamics, and pharmacokinetics of dalbavancin. We also discuss its development process, highlighting efficacy and safety data from pertinent clinical trials and the role it could play in the current clinical landscape.

Expert opinion: DISCOVER 1 and DISCOVER 2 demonstrated dalbavancin’s non-inferiority to vancomycin followed by linezolid for ABSSSI and confirmed its safety and tolerability. They were among the first trials to use new, early primary efficacy endpoints, and dalbavancin was among the first agents designated a Qualified Infectious Disease Product for expedited review. Dalbavancin may prove to be a valuable option for ABSSSI patients in whom conventional therapy is limited.     

Apatinib for the treatment of gastric cancer

Introduction: Antiangiogenesis therapy plays an important role in cancer treatment. Apatinib mesylate, a small molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, has been recommended as third-line treatment for metastatic gastric cancer patients.

Areas covered: The current review summarizes the publications and conference reports relating to apatinib from preclinical and clinical research in gastric cancer. Apatinib showed good safety, tolerance and treatment efficacy in Phase I/II studies. In a Phase III study, apatinib prolonged the median overall survival of patients with chemotherapy-refractory metastatic gastric cancer by 55 days and the median progression-free survival by 25 days compared with placebo.

Expert opinion: Apatinib is a new treatment option for advanced gastric cancer. Apatinib is expected to have a broader application when it has been evaluated worldwide. The key issues are to find biomarkers and overcome drug resistance.     

Safety analysis of sofosbuvir and ledipasvir for treating hepatitis C

Introduction: The approval of sofosbuvir (SOF), a nucleotide analogue NS5B polymerase inhibitor, and ledipasvir (LDV), a NS5A inhibitor, marked a new chapter in IFN and ribavirin-free treatment of hepatitis C virus (HCV). This drug reduces adverse events associated with IFN therapy.

Areas Covered: The purpose of this paper is to evaluate the safety and efficacy of LDV/SOF. Clinical trials illustrating safety and efficacy of LDV/SOF are reviewed and compared to other IFN and ribavirin-free treatment options available.

Expert Opinion: In trials enrolling more than 3000 patients, LDV/SOF is well tolerated with a good safety and side-effect profile in diverse cohorts, including previous direct-acting antiviral (DAA) treatment failures, liver transplant recipients, decompensated cirrhosis and HIV/HCV co-infection. As with all DAAs, the potential for drug–drug interactions must be carefully evaluated, as demonstrated by recent post-marketing reports of symptomatic bradycardia when LDV/SOF is co-administered with amiodarone. Currently, dose recommendations cannot be given for patients with advanced renal disease. Trials in this population are ongoing, more study is warranted. When surveying the DAA regimens available, efficacy, safety and tolerability of LDV/SOF is comparable or better, and LDV/SOF provides an option with convenient single-tablet, once daily, ribavirin-free dosing with relatively few significant drug–drug interactions.     

Safety of vedolizumab in the treatment of Crohn’s disease and ulcerative colitis

Introduction: Vedolizumab is the latest FDA-approved anti-integrin therapy for treatment of moderate-to-severe inflammatory bowel disease (IBD). The safety and efficacy of vedolizumab have been studied in short-term clinical trials.

Areas covered: This paper reviews the safety profile of vedolizumab compared with other biologics. It also highlights the mechanism of action of the medication. We discuss the current position of vedolizumab in our current algorithm for IBD management and comment on future prospects of the drug.

Expert opinion: Vedolizumab appears to be a safe and effective option in the treatment of moderate-to-severe IBD in the short term. Long-term observational studies and post-marketing safety data are needed to ascertain the long-term efficacy and side effect profile.     

Evaluation of dolutegravir safety for the treatment of HIV-1

Introduction: Dolutegravir (DGV) is the newest integrase inhibitor approved for the treatment of HIV-1 infection in both treatment-naive and experienced adults and adolescents. This article reviews the safety of DGV for the treatment of HIV-1 infection.

Areas covered: The PubMed database was searched using the keywords ‘DGV’ and ‘HIV’. In addition, conference proceedings from Conference on Retroviruses and Opportunistic Infections, International AIDS Society and European AIDS Clinical Society meetings were searched for presentations on DGV clinical studies.

Expert opinion: DGV has demonstrated a favorable safety profile and is well tolerated for the treatment of HIV-1 infection. Unlike raltegravir, DGV can be given once daily, and unlike elvitegravir, it does not require pharmacologic boosting to achieve consistent blood levels.     

The clinical safety of ibrutinib in chronic lymphocytic leukemia

Introduction: Ibrutinib, a targeted inhibitor of B-cell receptor signaling, achieved impressive clinical results for patients with chronic lymphocytic leukemia (CLL). These results allowed the approval of ibrutinib for the treatment of patients with CLL who have received at least one prior therapy and those with a 17p deletion regardless of line of therapy.

Areas covered: Comprehensive data from either Phase I-II or randomized Phase III studies are analyzed in this article. In addition, we reviewed data on the prevalence and the clinical management of some peculiar toxicities ibrutinib related such as lymphocytosis, major bleeding and atrial fibrillation.

Expert opinion: Ibrutinib has radically changed the scenery of relapsed/refractory CLL treatment and established an important paradigm in the molecularly targeted approach of this disease. Discontinuation of ibrutinib is rarely due to adverse events related to the drug. Patients who discontinue treatment represent a challenge to the physicians because treatment options are very limited.     

Future of combination therapy with dabrafenib and trametinib in metastatic melanoma

Introduction: Combination therapy with BRAF and MEK inhibitors is a recommended treatment strategy for metastatic melanoma patients with BRAF^V600 mutations. This treatment provides significant response rates and little added toxicity, with relatively improved survival outcomes compared to RAF/MEK inhibitor monotherapy and chemotherapy.

Areas covered: This review covers the pharmacology, efficacy, and toxicity data derived from clinical studies of dabrafenib, trametinib, and the combination thereof. The major downfall of combiDT is the limited durability of response, which is largely due to acquired resistance in the MAPK pathway.

Expert opinion: Future directions of combiDT concentrate on further combinations with immunotherapy or other targeted inhibitors, referred to triple-agent therapy, which may be essential to improving durability of responses and overcoming resistance.     

Safety of infliximab for the treatment of inflammatory bowel disease: current understanding of the potential for serious adverse events

Introduction: Infliximab, a chimeric monoclonal antibody directed towards TNF-α, has revolutionized the treatment of inflammatory bowel disease (IBD). Since this therapy suppresses the immune system by neutralizing the immunological activity of TNF, concerns exist regarding the potential for infection, malignancy and immune disorders.

Areas covered: Comprehensive data from randomized controlled trials, meta-analyses and cohort studies have defined the risk of infection and malignancy with infliximab. Additional data regarding associations with immune disorders, such as drug-induced lupus, demyelinating syndromes and psoriaform skin disease have emerged, primarily from case reports. We report evidence from the most robust data sources that have examined these adverse events.

Expert opinion: A modest increase in the incidence of serious infection with infliximab and TNF-antagonists has been observed in methodologically rigorous studies. Combination therapy with an immunosuppressant does not confer a higher risk of serious infection than infliximab monotherapy. TNF-antagonist therapy alone with an immunosuppressant is not associated with higher rates of malignancy. Additional data are required to define causality, the magnitude and determinants of risk for other immune-related complications. Available data suggest the therapeutic index of infliximab is favorable for treatment of moderate-to-severe IBD.     

Assessing safety and efficacy of sofosbuvir for the treatment of hepatitis C

Introduction: IFN-free regimens with direct antiviral agents (DAAs) against hepatitis C virus (HCV) are likely to greatly expand patients’ access and response to hepatitis C therapy, while safety and tolerability of treatments seem substantially improved. Sofosbuvir (SOF), a NS5B nucleotide polymerase inhibitor with pan-genotypic activity and a high-barrier to resistance, has been approved by FDA and EMA in an all oral combination therapy for chronic hepatitis C with ribavirin (RBV) alone, or in combination with either pegylated interferon/RBV or other DAAs.

Areas covered: This paper provides an overview of SOF-based therapy in chronic hepatitis C as it emerges from the published clinical trials. Data on special populations are included (i.e., decompensated patients, patients on liver transplant waiting lists, patients with renal impairment). The data has been analyzed according to the different HCV-genotypes and comprehensively covers both safety and efficacy treatment profiles.

Expert opinion: Clinical trials have highlighted the safety and efficacy of SOF-based regimens, leading to the rapid approval of this therapy and its incorporation in the recommendations of the international societies on treatment of HCV infection. However, additional data are still needed to optimize both combination therapies’ efficacy and duration in some categories of patients who have been under-represented in the registration trials.     

Solabegron: a potential future addition to the β-3 adrenoceptor agonist armamentarium for the management of overactive bladder

Introduction: Overactive bladder (OAB) affects many women and men worldwide and has a significant adverse effect on a person’s quality of life. Historically, behavioral therapy and anti-muscarinic agents have been the primary therapies used in the management of OAB. However, persistence with anti-muscarinic therapy has been limited. The role of β-3 agonists is established in the management of OAB with the first β-3 agonist recently approved by the FDA. Solabegron is one such selective β-3 agonist currently under investigation.

Areas covered: In this review, the authors discuss animal studies, in vitro human bladder strip and Phase II studies, which suggest a role for solabegron in the management of OAB. The authors also discuss its potential role in combination therapy.

Expert opinion: Phase II studies with solabegron support its potential future role in the management of OAB. However, further studies are needed to establish its efficacy and safety as well as to allow its clinical comparison with current therapies.     

Drug safety evaluation of apremilast for treating psoriatic arthritis

Introduction: Apremilast is an orally available small molecule that targets PDE4. PDE4 modulates intracellular signaling and thereby can impact various proinflammatory and anti-inflammatory mediators. Apremilast has been approved by the USA FDA for the treatment of active psoriatic arthritis (PsA) and moderate-to-severe psoriasis (PsO). Although there are several therapies approved and used for the treatment of PsA, there is still an unmet need for additional effective and well-tolerated therapeutic options. In PsA clinical trials, apremilast has been shown to be efficacious and to have an acceptable safety profile.

Areas covered: This review article covers the mechanism of action of apremilast, its efficacy in clinical trials and a detailed focus on its safety profile, mainly from Phase III clinical trials.

Expert opinion: Based on the available literature, apremilast has proven to be an efficacious therapy for PsA and PsO. It may offer some advantage as compared to other therapeutic options given its favorable safety profile, including a lack of need for routine laboratory monitoring.     

Not everything about atrial fibrillation is a hot topic: drug-induced atrial fibrillation is an exception

Introduction: Amphotericin B (AmB) was first approved by the US Food and Drug Administration in 1959 with sodium deoxycholate (DAmB, Fungizone®). Extensive toxicities associated with the drug led to the development of lipid formulations of AmB, including liposomal amphotericin B (L-AmB, AmBisome®). Phase I studies as well as comparative Phase III clinical trials indicate that L-AmB is associated with less nephrotoxicity and reduced infusion-related toxicity. There is, however, no recent comprehensive review of the safety and tolerability of L-AmB.

Areas covered: This article reviews the safety, tolerability and the mechanisms of the major toxicities associated with L-AmB, including nephrotoxicity, infusion-related reactions (IRRs), anemia and thrombocytopenia, and hepatic abnormalities. The article further discusses the mechanism of action and pharmacokinetics of L-AmB.

Expert opinion: L-AmB is a broad-spectrum antifungal agent that has significantly reduced toxicities compared to its predecessor, DAmB.     

Dasabuvir: a new direct antiviral agent for the treatment of hepatitis C

Introduction: Treatment of hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) has revolutionized the care of infected patients. Among these novel compounds are non-nucleoside analogs, which bind viral RNA-dependent RNA polymerase resulting in a conformational change inhibiting RNA synthesis.

Areas covered: Efficacy and tolerability of treatment regimens containing the non-nucleoside analog polymerase inhibitor dasabuvir (ABT-333).

Expert opinion: Dasabuvir-containing regimens achieve high rates of sustained virologic response in HCV genotype 1a and 1b–infected patients when combined with other DAAs, namely paritaprevir (ABT-450), ritonavir and ombitasvir (ABT-267). In the populations studied, dasabuvir seems to be well tolerated and safe. The major limitations of this novel drug are its genotype-restricted activity, the necessity to include ribavirin for HCV genotype 1a and the emergence of resistance if not combined with other DDAs.     

Tigecycline: a critical safety review

Introduction: The emergence of multidrug-resistant (MDR) infections has been extensively observed worldwide and has become a priority issue over past decade. Tigecycline, a broad spectrum antibiotic covering against many MDR organisms, has been widely used. However, recent meta-analysis studies have raised a concern for its efficacy and safety. Reviewing tigecycline safety data would enhance the appropriate use of this medication.

Areas covered: This article reviews the safety profile of tigecycline, including its side effects and drug interactions.

Expert opinion: The increased mortality associated with tigecycline is not yet well understood. Based on current evidence, alternative options must be prioritized over tigecycline if available. When tigecycline use is warranted, vigilant observation to identify any breakthrough infections and careful monitoring of progression of the original infection are highly recommended. Considering a second agent (either for synergism or enhancing coverage) may be required.     

Tiotropium bromide as add-on therapy to inhaled corticosteroids for treating asthma

Introduction: Bronchial asthma is becoming increasingly prevalent worldwide. Although first-line therapy with inhaled corticosteroids (ICS) with or without long-acting β2 agonists (LABA) has significantly improved the clinical outcomes of asthma, they cannot provide all asthmatics with good control and thus alternatives or add-on drugs are required. Tiotropium is a long-acting muscarinic antagonist that has been used to treat chronic obstructive pulmonary disease and it has been approved for treating asthma in some countries. This agent has similar bronchodilatory effects to those of LABA and might also have anti-inflammatory and anti-remodeling effects.

Areas covered: Some pivotal clinical trials have found tiotropium effective as an add-on medication for low-to-medium doses of ICS for treating symptomatic asthma and asthma that remains uncontrolled despite ICS plus LABA therapy.

Expert opinion: Whether or not tiotropium has anti-inflammatory and anti-remodeling effects in humans with asthma is an important issue. Predictors that would identify patients who would derive the maximal potential benefit from treatment with tiotropium in addition to their current therapy are also needed. Although the cardiovascular toxicity of tiotropium is less remarkable in asthma than in chronic obstructive pulmonary disease, longer and larger studies are still needed to confirm the safety of tiotropium for treating asthma.     

Odanacatib for the treatment of osteoporosis

Introduction: Osteoporosis and fragility fractures are important public health concerns. Cathepsin K inhibitors, including odanacatib, are a novel class of medications for osteoporosis whose mechanism of action is to directly inhibit bone resorption without killing osteoclasts, thereby permitting the complex coupling between bone resorption and formation to continue.

Areas covered: The physiological basis for the mechanism of action of cathepsin K inhibitors is covered in addition to a review of the preclinical, Phase I, Phase II and preliminary Phase III trial data of odanacatib.

Expert opinion: Evidence suggests that odanacatib has similar efficacy to bisphosphonates at increasing bone mineral density and decreasing risk of fragility fractures. Although odanacatib may preferentially inhibit bone resorption more than formation, the clinical significance of this difference in mechanism of action is not yet known. A careful analysis of the Phase III trial data is needed with specific attention to adverse events.     

Glargine safety,diabetes and cancer

Introduction: Denosumab is a fully human monoclonal antibody against the receptor activator of nuclear factor kappa-B ligand. It is an antiresorptive agent that reduces osteoclastogenesis.

Areas covered: This drug evaluation reviews denosumab for use in osteoporosis. Denosumab has been shown to improve bone mineral density (BMD) and to reduce the incidence of new vertebral, hip and nonvertebral fractures in postmenopausal women. It prevents bone loss and reduces vertebral fracture risk in men with nonmetastatic prostate cancer who are receiving androgen deprivation therapy. It has also been shown to improve BMD in men with osteoporosis unrelated to androgen deprivation therapy. Safety concerns include infections, cancer, skin reactions, cardiovascular disease, hypocalcemia, osteonecrosis of the jaw and atypical femur fractures.

Expert opinion: Although bisphosphonates are typically preferred as initial therapy for osteoporosis, denosumab could be used as initial therapy in select patients at high risk for fracture, including older patients who have difficulty with the dosing requirements of oral bisphosphonates, patients who are intolerant of or unresponsive to other therapies, and in those with impaired renal function. Additional data is needed to address issues regarding treatment duration and discontinuation, as well as to provide more information regarding denosumab's efficacy and safety.     

Apremilast: a PDE4 inhibitor for the treatment of psoriatic arthritis

Introduction: The evidence base for disease-modifying anti-rheumatic drugs used in psoriatic arthritis (PsA) is surprisingly weak, with most having little robust evidence to support their clinical use. Furthermore, there remain safety and tolerability concerns with both these and more recently available biological therapies. Apremilast, a novel, small molecule, represents the first oral therapy specifically developed for PsA.

Areas covered: This review describes the pharmacokinetic properties of apremilast and available data demonstrating significant benefits to both clinical and histological features of inflammatory arthritis. The key findings from a large Phase III clinical program will also be discussed, including short- and long-term efficacy outcomes and, importantly, the safety profile. Indications other than PsA will also be briefly reviewed. Given the recent nature of much of the data, published literature as well as information available only in the abstract format are included in this review.

Expert opinion: Studies show that treatment with apremilast results in significant improvement in both skin psoriasis and PsA symptoms. Apremilast has been approved by both the United States FDA and European Medicines Agency for treatment of PsA. Use of this medication is recommended in active PsA patients, according to local licensing.